The present invention relates to a new process for the large-scale preparation of ene-amide derivatives useful as valuable substrates for asymmetric hydrogenation reaction and hence for the synthesis of enantiomerically pure amines derivatives known as key intermediates for active pharmaceuticals.
Several methods have been described in the prior art, for example in WO 99/18065 to prepare ene-amide precursors, but these methods are clearly not very general and unsuitable for large-scale production.
The articles JOC, 1998, 63, p 6084 of the authors M. Burk and Coll. and JOC, 1999, 64(6), p 1775 of the authors X. Zhang and Coll. describe a process for ene-amide compounds synthesis comprising the reduction of oxime derivatives with iron metal in presence of acetic anhydride/acetic acid or acetic anhydride only.
The U.S. Pat. No. 4,194,050 patent describes a process for ene-amide compounds synthesis comprising the reduction of oxime derivatives with ruthenium catalyst in presence of carboxylic anhydride.
However, these processes show some limitations such as product decomposition under these conditions, use of co-solvent to facilitate product isolation, impure ene-amides which required arduous purifications and low to moderate yields.
Prior art processes are unsuitable for large-scale production of ene-amide derivatives and hence not applicable to the commercial preparation of chiral amines via asymmetric hydrogenation.